Glycosaminoglycans, with the exception of hyaluronic acid, are the degradation products of proteoglycans that exist in the extracellular matrix. Proteoglycans enter lysosomes for intracellular digestion, thereby generating glycosaminoglycans (GAGs).
The mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the stepwise degradation of GAGs (previously called mucopolysaccharides). An inability or decreased ability to degrade GAGs results in characteristic intralysosomal accumulation in all cells and increased excretion in urine of partially degraded GAGs. As substrates accumulate, the lysosomes swell and occupy more and more of the cytoplasm, affecting cellular organelles. The accumulation of GAGs ultimately results in cell, tissue, and organ dysfunction.
There are at least four different pathways of lysosomal degradation of GAGs, depending on the molecule to be degraded (e.g., dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate). The stepwise degradation of GAGs requires at least 10 different enzymes: four glycosidases, five sulfatases, and one nonhydrolytic transferase. Deficiencies of each one of these enzymes have been reported and result in seven different MPSs of various subtypes, all of which share several clinical features in variable degrees. Typical symptoms include organomegaly, dysostosis multiplex, and coarse facial features. Central nervous system function, including cognitive status, hearing, and vision, as well as cardiovascular function may also be affected. Many lysosomal storage disorders affect the nervous system and thus demonstrate unique challenges in treating these diseases with traditional therapies. There is often a large build-up of glycosaminoglycans (GAGs) in neurons and meninges of affected individuals, leading to various forms of CNS symptoms. To date, no CNS symptoms resulting from a lysosomal disorder has successfully been treated by any means available.
One such MPS disease is Mucopolysaccharidoses IIIA (MPS IIIA), which is also known as Sanfilippo Syndrome Type A. It is an autosomal recessive disease caused by a mutation in the SGSH gene, which encodes heparan N-sulfatase. Over 70 different mutations in SGSH have been described, all of which cause enzyme defects resulting in the accumulation of heparan sulfate. MPS IIIA occurs once in about every 100,000 live births, with no ethnic predisposition noted.
The primary accumulation of the GAG heparan sulfate triggers a poorly understood pathological cascade, primarily affecting the central nervous system (CNS). Mechanisms of pathology include secondary accumulation of toxic metabolites, neuroinflammation, disrupted growth factor signaling and dysregulated cell death. The clinical features of MPS IIIA are overwhelmingly neurological, with developmental delays in mid- to late-infancy often being the first manifestation of disease. Severe behavior disturbances are a frequent feature of middle childhood, with progressive dementia, emotional withdrawal and developmental regression. Afflicted individuals typically do not survive past their early twenties.
Enzyme replacement therapy (ERT) involves the systemic administration of natural or recombinantly-derived proteins and/or enzymes to a subject. Approved therapies are typically administered to subjects intravenously and are generally effective in treating the somatic symptoms of the underlying enzyme deficiency. As a result of the limited distribution of the intravenously administered protein and/or enzyme into the cells and tissues of the central nervous system (CNS), the treatment of diseases having a CNS etiology has been especially challenging because the intravenously administered proteins and/or enzymes do not adequately cross the blood-brain barrier (BBB).
The blood-brain barrier (BBB) is a structural system comprised of endothelial cells that functions to protect the central nervous system (CNS) from deleterious substances in the blood stream, such as bacteria, macromolecules (e.g., proteins) and other hydrophilic molecules, by limiting the diffusion of such substances across the BBB and into the underlying cerebrospinal fluid (CSF) and CNS.
There are several ways of circumventing the BBB to enhance brain delivery of a therapeutic agent including direct intra-cranial injection, transient permeabilization of the BBB, and modification of the active agent to alter tissue distribution. Direct injection of a therapeutic agent into brain tissue bypasses the vasculature completely, but suffers primarily from the risk of complications (infection, tissue damage, immune responsive) incurred by intra-cranial injections and poor diffusion of the active agent from the site of administration.
To date, direct administration of proteins into the brain substance has not achieved significant therapeutic effect due to diffusion barriers and the limited volume of therapeutic that can be administered. Convection-assisted diffusion has been studied via catheters placed in the brain parenchyma using slow, long-term infusions (Bobo, et al., Proc. Natl. Acad. Sci. U.S.A 91, 2076-2080 (1994); Nguyen, et al. J. Neurosurg. 98, 584-590 (2003)), but no approved therapies currently use this approach for long-term therapy. In addition, the placement of intracerebral catheters is very invasive and less desirable as a clinical alternative.
Intrathecal (IT) injection, or the administration of proteins to the cerebrospinal fluid (CSF), has also been attempted but has not yet yielded therapeutic success. A major challenge in this treatment has been quantifying clinical efficacy. Currently, there are no approved products for the treatment of brain genetic disease by administration directly to the CSF.
Thus, there remains a great need for effective and clinically quantifiable treatment of lysosomal storage diseases. More particularly, there is a great need for optimized therapeutic regimens of enzyme replace therapies capable of achieving measurable clinical efficacy, such as improvement, stabilization or reduction in decline of cognitive function, disability, behavior, quality of life and/or auditory brainstem response.